DK154139B - METHOD FOR PREPARING 4-HYDROXY-2-METHYL-2H-1,2-BENZOTHIAZINE-1,1-DIOXIDE-3-CARBOXYLIC ACID DERIVATIVES CONVERSIBLE TO PIROXICAM - Google Patents
METHOD FOR PREPARING 4-HYDROXY-2-METHYL-2H-1,2-BENZOTHIAZINE-1,1-DIOXIDE-3-CARBOXYLIC ACID DERIVATIVES CONVERSIBLE TO PIROXICAM Download PDFInfo
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- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Description
DK 154139 Β ίDK 154139 Β ί
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af 4-hydroxy-2-methyl-2H-1,2-benzothiazin-1,1-dioxid-3-carboxylsyrederivater, der kan omdannes til det anti inflammatoriske middel piroxicam.The present invention relates to a particular process for the preparation of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid derivatives which can be converted into the anti-inflammatory agent piroxicam.
5 Piroxicam, et stærkt virkende antiinflammeto- risk middel, blev først rapporteret af Lombardino i USA-patentskrift nr. 3.591.584. En af de i patentskriftet beskrevne fremgangsmåder til syntese af piroxicam består i at omsætte en 3-carboxylsyreester med 1 o 2-aminopyridin. Mere specielt er esteren omtalt som en (C^-Cj^Jalkylester eller phenyl(C^_3)alkylester.5 Piroxicam, a potent anti-inflammatory agent, was first reported by Lombardino in U.S. Patent No. 3,591,584. One of the methods described in the patent for the synthesis of piroxicam consists of reacting a 3-carboxylic acid ester with 1 o 2-aminopyridine. More particularly, the ester is referred to as a (C ^-Cj ^alkyl ester or phenyl (C ^ _3) alkyl ester.
Den særlige ester, der er beskrevét er methylesteren, nemlig 0H Pi 15 Λ o o [se også Lombardino et al., j. Med. Chem. 14, s. 1171-20 1175 (1975)].The particular ester described is the methyl ester, namely 0H Pi 15 Λ o o [see also Lombardino et al., J. With. Chem. 14, pp. 1171-20 1175 (1975)].
I et nyere USA-patentskrift, nr. 4 289 879 er oplyst, at den tilsvarende 2-methoxyethylester med visse fordele kan benyttes i stedet for 2-methylesteren ved omsæt- 25 ningen med 2-aminopyridin.In a recent U.S. Patent No. 4,289,879, it is stated that the corresponding 2-methoxyethyl ester, with certain advantages, can be used instead of the 2-methyl ester in the reaction with 2-aminopyridine.
Andre alternative synteser af piroxicam, der er blevet beskrevet i litteraturen,omfatter omsætning af 3,4-dihydro-2-methyl-4-oxo-2H-l,2-benzothiazin-lf1-dioxid med 2-pyridylisocyanat (Lombardino, USA-patent-30 skrift nr. 3.591.584), transamidering af 4-hydroxy-2-methyl-2H-l,2-benzothiazin-2-carboxahilider med 2-ami-nipyridin (Lombardino, USA-patentskrift nr. 3.891.637), cyclisering af aC02<cl-C3) alkylOther alternative syntheses of piroxicam that have been described in the literature include reacting 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-1H-dioxide with 2-pyridylisocyanate (Lombardino, USA). Patent No. 3,591,584), transamidation of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-2-carboxahilides with 2-aminipyridine (Lombardino, U.S. Patent No. 3,891,637) , cyclization of αCO2 (C1-C3) alkyl
S02NCH2C0NHS02NCH2C0NH
ch3CH3
DK 154139 BDK 154139 B
2 (Lombardino, USA-patentskrift nr. 3.853.862), kobling af et 4-(C-^-C-j) alkoxy-2-methyl-2H-l,2-benzothiazin-3-carb-oxylsyre-1,1·-dioxid med 2-aminopyridin efterfulgt af hydrolyse af enoletherbindingen (Lombardino, USA-patent-5 skrift nr. 3.892.740), kobling af 4-hydroxy-2-methyl-2H-l,2-benzothiazin-3-carboxylsyre, via syrechloridet, med 2-aminopyridin (Hammen, USA-patentskrift nr. 4.100.347) og methylering af 4-hydroxy-N-2-pyridyl-2H-1,2-benzothiazin-3-carboxamid (canadisk patent’ll skrift nr. 1.069.894) samt af 4-hydroxy-N-2-pyridyl-2H- 1,2-benzothiazin-3-carboxamid-1,1-dioxid (Zinnes et al.2 (Lombardino, U.S. Patent No. 3,853,862), coupling a 4- (C --Cj) alkoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid-1,1 · -dioxide with 2-aminopyridine followed by hydrolysis of the enol ether bond (Lombardino, U.S. Patent No. 3,892,740), coupling of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid, via the acid chloride, with 2-aminopyridine (Hammen, U.S. Patent No. 4,100,347) and methylation of 4-hydroxy-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide (Canadian Patent Specification 1,069,894) as well as of 4-hydroxy-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (Zinnes et al.
USA patentskrift nr. 4 074 048)U.S. Patent No. 4,074,048)
Den foreliggende opfindelse angår en fremgangsmåde til fremstilling af forbindelser med 1 5 den almene formelThe present invention relates to a process for the preparation of compounds of the general formula
OHOH
^^Λγ·°°-κα 20 „ SCH, °2 3 hvori er alkoxy med 1 til 4 carbonatomer eller 2-methoxyethoxy, hvilken fremgangsmåde består i at omsætte en forbindelse med den almene formel 25 XNT ft HO.^-11—Rj l 1 /N“CH3 11 30 o2 hvori X er chlor, brom eller iod, med et ækvivalent af et metalhydrid i et polært reaktions-indifferent opløsningsmiddel ved fra ca. 25°C til ca. 50?C, indtil omsætningen er i det væsentlige fuldstændig.Wherein: is alkoxy of 1 to 4 carbon atoms or 2-methoxyethoxy, the process of which is to react a compound of the general formula 25 XNT ft HO in which X is chlorine, bromine or iodine, with an equivalent of a metal hydride in a polar reaction-inert solvent at from ca. 25 ° C to approx. 50 ° C until the turnover is essentially complete.
3535
DK 154139 BDK 154139 B
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Et foretrukket træk ved denne fremgangsmåde er anvendelsen af et reaktions-indifferent opløsningsmiddel valgt blandt dimethylformamid, dimethylacetamid, dimethylsulfoxid, hexamethylphosphoramid og 1-methyl-5 2-pyrrolidon.A preferred feature of this process is the use of a reaction inert solvent selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide and 1-methyl-5-2-pyrrolidone.
Et andet foretrukket træk ved denne fremgangsmåde er udvælgelsen af et metalhydrid blandt kalium-hydrid, natriumhydrid og calciumhydrid.Another preferred feature of this process is the selection of a metal hydride from potassium hydride, sodium hydride and calcium hydride.
Et specielt foretrukket træk ved denne frem-10 gangsmåde er anvendelsen af et udgangsreagens, hvori X er chlotr anvendelsen som reaktions-indifferent op- løsningsmiddel af dimethylformamid eller dimethyl-sulfoxid, anvendelsen af natriumhydrid som metalhydri-det og anvendelsen af en forbindelse, hvori er 15 methoxy eller 2-methoxyethoxy.A particularly preferred feature of this process is the use of an starting reagent wherein X is the chlorine use as the reaction-inert solvent of dimethylformamide or dimethylsulfoxide, the use of sodium hydride as the metal hydride, and the use of a compound wherein Methoxy or 2-methoxyethoxy.
Forbindelserne fremstillet ved denne fremgangsmåde er nyttige mellemprodukter, der fører til piroxi-cam som beskrevet i de ovenfor nævnte litteratursteder.The compounds prepared by this process are useful intermediates leading to piroxy cam as described in the above-mentioned literature sites.
Denne fremgangsmåde har den fordel, at de ønske- 20 de produkter opnås i højt udbytte, og man undgår også nødvendigheden af methylering af 4-hydroxy-2H-l,2-ben-zothiaz inringsystemet.This process has the advantage that the desired products are obtained in high yield and also avoids the necessity of methylation of the 4-hydroxy-2H-1,2-benzothiaz ring system.
Som det vil være klart for fagmanden, kan de ved de her omhandlede fremgangsmåder fremstillede 25 forbindelser bestå i enten ketonformen eller den tau-tomere enolform:As will be appreciated by those skilled in the art, the compounds of the present invention may comprise either the ketone form or the tauomeric enol form:
O O OHO O OH
30 QCJ —* OCX30 QCJ - * OCX
02 CH3 ' 02 302 CH3 '02 3
Det vil være klart for fagmanden, at disse former 25 er ækvivalente. Den foreliggende opfindelse skal omfatte begge tautomere former, men for simpelheds skyld skrives kun den ene af disse.It will be appreciated by those skilled in the art that these forms are equivalent. The present invention should encompass both tautomeric forms, but for simplicity only one of them is written.
DK 154139BDK 154139B
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Fremgangsmåden ifølge den foreliggende opfindelse, der leder til mellemprodukter, der er nyttige til syntesen af det antiinflammatoriske middel piroxicam, kan anskueliggøres son _ følger: 5The process of the present invention which leads to intermediates useful for the synthesis of the anti-inflammatory agent piroxicam can be illustrated as follows:
XX
H0 0HH0 0H
0C\C0Rl ,o " o2 -3 hvori X og har den ovenfor angivne betydning.0C \ C0R1, o "o2 -3 wherein X and has the meaning given above.
Fremgangsmåden består i at omsætte et mol af en passende 1,2-benzisosulfonazol med et ækvivalent af et metalhydrid i et polært reaktions-indifferent opløsningsmiddel. Der kan benyttes et vilkårligt metalhydrid,omend alkalimetalhydrider og jordalkali-metalhydrider foretrækkes, da mange af disse er til-gangelige i handelen eller let kan fremstilles. Særligt foretrukne er natriumhydrid, kaliumhydrid og calcium-hydrid.The process consists of reacting one mole of a suitable 1,2-benzisosulfonazole with an equivalent of a metal hydride in a polar reaction-inert solvent. Any metal hydride may be used, although alkali metal hydrides and alkaline earth metal hydrides are preferred as many of these are commercially available or readily prepared. Particularly preferred are sodium hydride, potassium hydride and calcium hydride.
Denne fremgangsmåde udføres også i et reaktionsindifferent opløsningsmiddel. Et sådant opløsningsmiddel, eller blandinger deraf, skal tjene til at opløse-25 liggøre reaktanterne i en sådan grad, at reaktionen lettes, men bør ikke reagere med reagenserne eller produktet i kendelig grad. Sådanne opløsningsmidler bør også være stærkt polære opløsningsmidler med en dielektricitetskonstant (e) =35. Disse opløsningsmidler omfatter sådanne foretrukne opløsningsmidler som di-methylsulfoxid, dimethylformamid, dimethylaeetamid, l-methyl-2-pyrrolidon og hexamethylphosphoramid.This process is also carried out in a reaction inert solvent. Such a solvent, or mixtures thereof, should serve to dissolve the reactants to such an extent that the reaction is facilitated, but should not react with the reagents or product to any appreciable extent. Such solvents should also be highly polar solvents with a dielectric constant (e) = 35. These solvents include such preferred solvents as dimethylsulfoxide, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone and hexamethylphosphoramide.
Med hensyn til foreningen af reagenserne kan __ det passende metalhydrid sættes til den fornødne 1,2-benzisosulfonazol i et reaktions-indifferent opløsningsmiddel, eller 1,2-benzisosulfonazolen kan i det reaktions-indifferente opløsningsmiddel sættes til enWith respect to the compound of the reagents, the appropriate metal hydride can be added to the required 1,2-benzisosulfonazole in a reaction-inert solvent, or the 1,2-benzisosulfonazole can be added to the reaction-inert solvent.
DK 154139 BDK 154139 B
5 suspension af metalhydridet i det reaktionsindifferente opløsningsmiddel.5 suspension of the metal hydride in the reaction-inert solvent.
Efter at reagenserne er bragt sammen opvarmes reaktionsblandingen til reaktionstemperaturen på fra ^ o o ca. 25 C til ca. 50 C. Reaktionstemperaturer lavere end eller højere vil føre til produkt, men vil have en skadelig virkning på udbytter og på produktets renhed og de frembyder ingen væsentlige fordele. Ved de fore-^q trukne reaktionstemperaturer er reaktionen fuldstændig i løbet af ca. 1/2 til 3 timer.After the reagents are brought together, the reaction mixture is heated to the reaction temperature of about 25 C to approx. 50 C. Reaction temperatures lower than or higher will lead to product, but will have a detrimental effect on yields and on the purity of the product and offer no significant benefits. At the preferred reaction temperatures, the reaction is complete within approx. 1/2 to 3 hours.
Efter at reaktionen er afsluttet afkøles blandingen hurtigt i kold 5%'s saltsyre, og produktet filtreres eller ekstraheres med et med vand ublandbart 15 opløsningsmiddel såsom methylenchlorid. Det efter fjernelse af ekstraktionsopløsningsmidlet tilbageværende produkt eller det ved filtrering opnåede produkt kan renses på kendt måde,eller det kan uden yderligere rensning anvendes til fremstillingen af piroxicam.After the reaction is complete, the mixture is rapidly cooled in cold 5% hydrochloric acid and the product is filtered or extracted with a water-immiscible solvent such as methylene chloride. The product remaining after removal of the extraction solvent or the product obtained by filtration can be purified in known manner or it can be used for the preparation of piroxicam without further purification.
2q Et foretrukket træk ved denne fremgangsmåde er anvendelsen af sådanne reagenser, hvori X er chlor, anvendelse som reaktions-indifferent opløsningsmiddel af dimethylformamid eller dimethylsulfoxid og anvendelse af natriumhydrid som metalhydridet.2q A preferred feature of this process is the use of such reagents in which X is chlorine, use as a reaction inert solvent of dimethylformamide or dimethyl sulfoxide, and use of sodium hydride as the metal hydride.
25 Særligt foretrukket er fremstillingen ved denne fremgangsmåde af produkter, hvori er methoxy eller 2-methoxyethoxy.Particularly preferred is the preparation by this process of products which are methoxy or 2-methoxyethoxy.
Udgangsreagenserne for fremgangsmåden ifølge foreliggende opfindelse kan let fremstilles ved 30 at omsætte et mol N-methylsaccharin med et mol af et passende halogenacetat i nærværelse af to ækvivalenter af et metalhydrid såsom natriumhydrid i et reaktionsindifferent opløsningsmiddel såsom tetrahydrofuran, som anskueliggjort nedenfor: 35The starting reagents of the process of the present invention can be readily prepared by reacting one mole of N-methylsaccharin with one mole of a suitable halogen acetate in the presence of two equivalents of a metal hydride such as sodium hydride in a reaction inert solvent such as tetrahydrofuran, as illustrated below:
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o HO Ro HO R
Γ li N-CH3 + XC^C-Rj-► Γ \T N-CH3 °2 I praksis behandles en opløsning af N-methyl- saccharin i tetrahydrofuran med to ækvivalenter natrium- 1 Ω hydrid og den resulterende reaktionsblanding opvarmes til ca. 40°C. Det pågældende alkyl- eller 2-methoxy-ethylhalogenacetat tilsættes i løbet af en periode på ca. 1 time, og reaktionsblandingen opvarmes i flere timer ved 40 til 50°C, efter at tilsætningen er tilende- 15 bragt. Efter fuldendelse af reaktionen sættes blandingen til en kold 5%'s saltsyreopløsning, og alkyl- eller 2-methoxyethyl-2-(2-methyl-3-hydroxy-2,3-dihydro-l,2-benzisosulfonazol-3-yl)-2-ha]ogenacetatet enten filtreres og tørres eller ekstraheres med et med vand ublandbart 20 opløsningsmiddel såsom methylenchlorid. Om nødvendigt kan produktet renses på i og for sig kendt måde.In practice, a solution of N-methyl-saccharin in tetrahydrofuran is treated with two equivalents of sodium 1 Ω hydride and the resulting reaction mixture is heated to ca. 40 ° C. The appropriate alkyl or 2-methoxyethyl halogen acetate is added over a period of approx. 1 hour and the reaction mixture is heated for several hours at 40 to 50 ° C after the addition is complete. After completion of the reaction, the mixture is added to a cold 5% hydrochloric acid solution and alkyl or 2-methoxyethyl-2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl) The 2-ha] ogene acetate is either filtered and dried or extracted with a water-immiscible solvent such as methylene chloride. If necessary, the product can be purified in a manner known per se.
Produkterne fremstillet ved fremgangsmåden ifølge opfindelsen er nyttige mellemprodukter, der fører til piro- xicam ved fremgangsmåder, der er beskrevet her og/eller 25 beskrevet i de litteratursteder og patentskrifter, hvortil der er henvist i foreliggende beskrivelse.The products prepared by the process of the invention are useful intermediates which lead to pyroxicam by methods described herein and / or described in the literature sites and patents referred to in the present specification.
De følgende eksempler tjener til nærmere illustration af fremgangsmåden ifølge opfindelsen. De 30 kernemagnetiske resonansspektre (NMR) blev målt ved 60 MHz for opløsninger i deuterochloroform (CDCl^), perdeuterodimethylsulfoxid (DMSO-dg) eller deuteriumoxid (D20), hvis ikke andet er angivet, og topstillingerne er udtrykt i dele pr. million (ppm) "downfield" fra 35 tetramethylsilan eller natrium-2,2-dimethyl-2-silapen-tan-5-sulfonat. Der benyttes følgende forkortelser for topformer: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.The following examples serve to illustrate the method of the invention. The 30 nuclear magnetic resonance spectra (NMR) were measured at 60 MHz for solutions in deuterochloroform (CDCl ^), perdeuterodimethylsulfoxide (DMSO-dg) or deuterium oxide (D20), unless otherwise indicated, and the peak positions are expressed in parts per minute. million (ppm) "downfield" from tetramethylsilane or sodium 2,2-dimethyl-2-silapene-tan-5-sulfonate. The following abbreviations are used for top forms: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplied.
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Eksempel 1 2- Methoxyethyl-4-hydroxy-2-methyl-2H-l, 2-Ibenzothiazin- 3- carboxylat-lTl-dioxid (I;R^ = -OC^C^fiXCH^) A. 2-Methoxyetihyl-2- (2-methyl-3-hydroxy-2,,3-dihydro-l, 2-5 benzisosulfonazol-3-yl)-2-chloracetat (ilj; x = Cl,Example 1 2- Methoxyethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1T1-dioxide (I; R-= -OC ^C ^FIXCH ^) A. 2-Methoxyethylethyl-2 - (2-methyl-3-hydroxy-2,3,3-dihydro-1,2,5-benzisosulfonazol-3-yl) -2-chloroacetate (µl; x = Cl,
Rx = OCH2CR2OCH3) .Rx = OCH2CR2OCH3).
I en f: lamme tørret kolbe under en .nitrogenatmosfære anbragtes 11,6 g (0,24 mol) 50% inatrium-hydrid i en oliedispersion. Mineralolien Ibiev derpå 10 fjernet ved vask med pentan og dekantering,, og der blev tilsat 50 ml tør tetrahydrofuran. Til den resulterende suspension sattes 20 g (0,1 mol) "N-methylsaccharin i 30 ml af det samme opløsningsmiddel, og blandingen blev opvarmet til 40°C. 2-Methoxyethylchloracetat 15 (15,4 g, 0,1 mol) blev dråbevis sat til neaktionsblån- dingen i løbet af 1 time. Reaktionsblandingen blev holdt ved 40-50°C i 2 timer efter afslutning af tilsætningen. Reaktionen blev derpå langsomt (dæmpet i en kølet vel omrørt 5%'s saltsyreopløsning, ©g det resul-20 t er ende bundfald blev ekstraheret (4 x 1030 ml) med methylenchlorid. Ekstrakterne blev forenet, tørret over magnesiumsulfat og koncentreret i vakuum, hvorved man opnåede det rå ønskede produkt som en gul olie, 37,6 g.In a fully dried flask under a nitrogen atmosphere, 11.6 g (0.24 mole) of 50% sodium hydride was placed in an oil dispersion. The mineral oil Ibiev was then removed by washing with pentane and decanting, and 50 ml of dry tetrahydrofuran was added. To the resulting suspension was added 20 g (0.1 mole) of N-methylsaccharin in 30 ml of the same solvent and the mixture was heated to 40 ° C. 2-Methoxyethyl chloroacetate 15 (15.4 g, 0.1 mole) was added. The reaction mixture was kept at 40-50 ° C for 2 hours after completion of the addition and then slowly (quenched in a cooled well stirred 5% hydrochloric acid solution, -20 t final precipitate was extracted (4 x 1030 ml) with methylene chloride, the extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give the crude desired product as a yellow oil, 37.6 g.
25 Det rå produkt blev krystalliseret af methylen chlorid-hexan, hvorved opnåedes 22,75 g (655%) af produktet, smp. 125,5-126,5°C. En prøve blev yderligere renset ved omkrystallisation af methylenchlorid-hexan, smp. 133-135,5°C.The crude product was crystallized by methylene chloride-hexane to give 22.75 g (655%) of the product, m.p. 125.5-126.5 ° C. A sample was further purified by recrystallization from methylene chloride-hexane, m.p. 133 to 135.5 ° C.
30 NMR-Spekret (DMSO-dg) viste absorption ved 7,6-8,2 (m, 5H)., 5,1 (s, IH), 4,0 (m, 2H)?, 3,3 (m, 2H) , 3,1 (s, 3H) og 2,7 (s, 3H) ppm.NMR-Specified (DMSO-dg) showed absorption at 7.6-8.2 (m, 5H)., 5.1 (s, 1H), 4.0 (m, 2H), 3.3 (m , 2H), 3.1 (s, 3H) and 2.7 (s, 3H) ppm.
Analyse:Analysis:
Beregnet for C^H^gOgSNCl: C, 44,6; H, 4,¾¾ N, 4,0 35 Fundet : C, 44,3; H, 4,7¾ N, 4,0.Calculated for C CH H gOOSNCl: C, 44.6; H, 4, ¾¾ N, 4.0 Found: C, 44.3; H, 4.7¾ N, 4.0.
DK 154139BDK 154139B
8 B. 2-Methoxyethy1-4-hydroxy-2-methy1-2H-1,2-benzothia-zin-3-carboxylat-l,1-dioxid.8 B. 2-Methoxyethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide.
Til 280 mg (5,8 mmol) af 50% natriumhydriddispersion, der var blevet vasket med pentan, blev 5 sat 10 ml dimethylsulfoxid ved stuetemperatur. Til den resulterende suspension sattes 1,75 g (5 mmol) 2-methoxy-ethyl-2-(2-methyl-3-hydroxy-2,3-dihydro-l,2-benziso-sulfonazol-3-yl)-2-chloracetat. Reaktionsblandingen, hvis temperatur steg til 32°C, blev omrørt i 1 1/2 time 10 og blev derpå sat til 150 ml af en kold 5%'s saltsyreopløsning. Bundfaldet blev frafiltreret og tørret, 1,29 g (82,4%).To 280 mg (5.8 mmol) of 50% sodium hydride dispersion washed with pentane was added 10 ml of dimethylsulfoxide at room temperature. To the resulting suspension was added 1.75 g (5 mmol) of 2-methoxyethyl-2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisulfonazol-3-yl) -2 -chloracetat. The reaction mixture, whose temperature rose to 32 ° C, was stirred for 1 1/2 hours 10 and then added to 150 ml of a cold 5% hydrochloric acid solution. The precipitate was filtered off and dried, 1.29 g (82.4%).
NMR-Spektret (DMSO-dg) viste absorption ved 8,0 (m, 4H), 4,5 (m, 2H), 3,7 (m, 2H), 3,34 (s, 3H) og 15 2,90 (s, 3H) ppm.The NMR spectrum (DMSO-dg) showed absorption at 8.0 (m, 4H), 4.5 (m, 2H), 3.7 (m, 2H), 3.34 (s, 3H), and 2 90 (s, 3H) ppm.
Produktet kan ikke skelnes fra det,der er rapporteret i eksempel 1 og i USA-patentskrift nr.The product is indistinguishable from that reported in Example 1 and in U.S. Pat.
4 289 879.4 289 879.
Eksempel 2 20 A. Ved at følge fremgangsmåden ifølge eksempel 1A og gå ud fra N-methylsaccharin og henholdsvis 2- methoxyethylbrom- og iodacetat fremstilles henholdsvis 2-methoxyethyl-2-(2-methyl-3-hydroxy-2,3-dihydro- 1,2-benzisosulfonazol-3-yl)-2-bromacetat og 2-methoxy- 25 ethyl-2-(2-methyl-3-hydroxy-2,3-dihydro-l,2-benziso-sulfonazol-3-yl)-2-iodacetat.EXAMPLE 2 A. Following the procedure of Example 1A and starting from N-methylsaccharin and 2-methoxyethyl bromo and iodoacetate, respectively, 2-methoxyethyl-2- (2-methyl-3-hydroxy-2,3-dihydro-2) is prepared. 1,2-benzisosulfonazol-3-yl) -2-bromoacetate and 2-methoxyethyl-2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisulfonazol-3-yl) ) -2-iodoacetate.
B. Ved at gå ud fra det angivne 2-methoxyethyl-2- (2-methyl-3-hydroxy-2,3-dihydro-l,2-benzisosulfonazol- 3- yl)-2-halogenacetat, hydrid og opløsningsmiddel og 30 den angivne temperatur og anvende fremgangsmåden ifølge eksempel 11B fremstilles 2-methoxyethyl-4-hydroxy-2-methy1-2H-1,2-benzothiaz in-3-c arboxyla t-1,1-dioxid: 35B. Starting from the indicated 2-methoxyethyl-2- (2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl) -2-haloacetate, hydride and solvent and 30 at the indicated temperature and using the procedure of Example 11B, 2-methoxyethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine in 3-carboxyla t-1,1-dioxide is prepared: 35
DK 154139BDK 154139B
9 ΗΟ>νί-ο«ϊ€Η2)2ο<:Η3 Γ9 ΗΟ> νί-ο «ϊ € Η2) 2ο <: Η3 Γ
Metal hydrld / 3 opløsningsmiddel ^ 5 ^'^6 '* ScH3 2 X Metalhydrid Temp. 0 C. OpløsningsmiddelMetal hydride / 3 solvent ^ 5 ^ '^ 6' * ScH3 2 X Metal hydride Temp. 0 C. Solvent
Cl KH · 25 IDMF1Cl KH · 25 IDMF1
10 Cl CaH2 45 rDMF10 Cl CaH2 45 rDMF
Cl NaH 35 IDMAC2Cl NaH IDMAC2
Cl NaH 50 1-M-2-P3Cl NaH 50 1-M-2-P3
Cl KH 50 IHMPA4Cl KH 50 IHMPA4
Cl KH 40 IDMFCl KH 40 IDMF
15 Br NaH 35 IDMAC15 Br NaH 35 IDMAC
Br NaH 35 JDMSO5Br NaH 35 JDMSO5
Br KH 25 tDMFBr KH 25 tDMF
Br CaH2 50 iDMACBr CaH2 50 iDMAC
Br CåH 50 DMSOBr CaH 50 DMSO
20 Br KH 30 IHMPA20 Br KH 30 IHMPA
*DMF * dimethyl formamid 2 DMAC = dimethylacetamid 3l-M-2-P = 1-methyl-2-pyrrolidon 25 4HMPA = hexamethylphosphoramid 5 DMSO = dimethyl sul f oxid ** DMF * dimethyl formamide 2 DMAC = dimethylacetamide 3-1-M-2-P = 1-methyl-2-pyrrolidone 4HMPA = hexamethylphosphoramide 5 DMSO = dimethyl sulfide oxide *
Eksempel 3Example 3
Methyl-4-hydroxy-2-methyl-2H-l, 2-benzothic&zrin-3-carb-oxylat-l,l-dioxid (I; = OCH^.Methyl 4-hydroxy-2-methyl-2H-1,2-benzothicrazine-3-carboxylate-1,1-dioxide (I; = OCH
30 A. Me thyl-2- (2 -me thy 1 - 3 - hydroxy- 2,3-dihydro-l, 2-benz-isosulfonazol-3-yl) -2-chloracetat III; = OCH^) .A. Methyl 2- (2-methyl-1-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl) -2-chloroacetate III; = AND ^).
Til 9,2 g (0,19 mol) 50% natriumhydrid-olie-dispersion, der irar blevet vasket fri for mlie med pentan, blev under en nitrogenatmosfære sat 20 ml tør 35 tetrahydrofuran. Til den resulterende suspension sattes 15,9 g (0,08 mol) N-methylsaccharin i 50 ml af det samme opløsningsmiddel, og opslemningen blev opvarmetTo 9.2 g (0.19 mol) of 50% sodium hydride oil dispersion, which has been washed free of pentane, was added under a nitrogen atmosphere to 20 ml of dry tetrahydrofuran. To the resulting suspension was added 15.9 g (0.08 mol) of N-methylsaccharin in 50 ml of the same solvent and the slurry was heated.
DK 154139 BDK 154139 B
10 til 40°C. Der blev i løbet af 1 time tilsat methyl-chloracetat (7 ml, 0,08 mol) i 20 ml tør tetrahydro-furan, idet reaktionstemperaturen blev holdt ved 40-45°C. Efter afslutning af tilsætningen blev reaktionsblandin-5 gen omrørt ved 35-42°C i 4 timer. Reaktionsblandingen blev derpå dæmpet i 700 ml 5%’s saltsyreopløsning, og produktet blev ekstraheret med methylenchlorid (7 x 100 ml). De forenede ekstrakter blev vasket med en 5%'s saltsyreopløsning og en mættet saltopløsning og tørret 10 over magnesiumsulfat. Ved fjernelse af opløsningsmidlet i vakuum opnåedes 21 g af produktet som en tung olie, der størknede ved henstand.10 to 40 ° C. Methyl chloroacetate (7 ml, 0.08 mol) was added in 20 ml of dry tetrahydrofuran over 1 hour keeping the reaction temperature at 40-45 ° C. After completion of the addition, the reaction mixture was stirred at 35-42 ° C for 4 hours. The reaction mixture was then quenched in 700 ml of 5% hydrochloric acid solution and the product was extracted with methylene chloride (7 x 100 ml). The combined extracts were washed with a 5% hydrochloric acid solution and a saturated saline solution and dried over magnesium sulfate. Upon removal of the solvent in vacuo, 21 g of the product was obtained as a heavy oil which solidified on standing.
En portion blev tritureret med isopropanol, hvorved opnåedes et hvidt fast stof, smp. 122-125°C.A portion was triturated with isopropanol to give a white solid, m.p. 122-125 ° C.
15 NMR-Spektret (DMSO-dg) viste absorption ved 8,1-7,6 (m, 5H), 5,05 (s, IH), 3,45 (s, 3H) og 2,7 (s, 3H) ppm.The NMR spectrum (DMSO-dg) showed absorption at 8.1-7.6 (m, 5H), 5.05 (s, 1H), 3.45 (s, 3H) and 2.7 (s, 3H). ) ppm.
Analyse:Analysis:
Beregnet for C^H^OgNSCl: c, 43,2; H, 3,9; N, 4,6 20 Fundet : C, 43,1; H, 4,0; N, 4,6.Calcd for C CH ^ONSNSCl: c, 43.2; H, 3.9; N, 4.6 Found: C, 43.1; H, 4.0; N, 4.6.
B. Methyl-4-hydroxy-2-methyl-2H-l,2-benzothiazin-3-carboxylat-1,1-dioxid.B. Methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide.
Til 63 mg (0,0013 mol) natriumhydrid vasket fri for olie med pentan i 8 ml tør dimethylsulfoxid 25 sattes 400 mg (0,0013 mol) methyl-2-(2-methyl-3-hydroxy-2, 3 -dihydro-l,2-benzisosulfonazol-3-yl) -2-chloracetat i 8 ml dimethylsulfoxid. Reaktionsblandingen blev opvarmet ved 35°C i 1 time og 15 minutter og blev derpå dæmpet i 80 ml af en kold 5%'s saltsyreopløsning. Bund-30 faldet blev filtreret og tørret, hvorved opnåedes 280 mg (80%) af det ønskede produkt, smp. 162-163°C. Produktet kunne ikke skelnes fra det, der er rapporteret i USA-patentskrift nr. 3.591.584.To 63 mg (0.0013 mole) of sodium hydride washed free of oil with pentane in 8 ml of dry dimethylsulfoxide 25 was added 400 mg (0.0013 mole) of methyl 2- (2-methyl-3-hydroxy-2,3-dihydroxy). 1,2-Benzisosulfonazol-3-yl) -2-chloroacetate in 8 ml of dimethylsulfoxide. The reaction mixture was heated at 35 ° C for 1 hour and 15 minutes and then quenched in 80 ml of a cold 5% hydrochloric acid solution. The precipitate was filtered and dried to give 280 mg (80%) of the desired product, m.p. 162-163 ° C. The product was indistinguishable from that reported in U.S. Patent No. 3,591,584.
Eksempel 4Example 4
35 A. Ved at følge fremgangsmåden ifølge eksempel 3AA. Following the procedure of Example 3A
og gå ud fra N-methylsaccharin og det ønskede alkylhalogen-and starting from N-methylsaccharin and the desired alkyl halogen
DK 154139 BDK 154139 B
11 acetat opnås følgende 1,2-benzisosulfønazoleri s Uv“ “> °2 X "· ...... R1........11 acetate, the following 1,2-benzisosulfonazole acid is obtained Uv ““> ° 2 X "· ...... R1 ........
10 C1 · -och2ch3C1 · -och2ch3
Cl -0{CH2)2CH3Cl-O (CH2) 2CH3
Cl -OCH(CH3)2Cl - AND (CH 3) 2
Cl -0(CH2)3CH3 q -oc(ch3)2 15 d -och2ch(ch3)2Cl-0 (CH2) 3CH3 q -oc (ch3) 2 d -och2ch (ch3) 2
Br ~0CH3Br ~ OCH3
Br -OCH2CH3Br -OCH2CH3
Br -0(CH2)2CH3Br-O (CH2) 2CH3
Br -0(CH2)3CH3 20 Br -OCH2CH(CH3)2 i -och3 I -OCH2CH3 I -OCH(CH3)2 I -0(CH2)3CH3 25 I -OCH2CH(CH3)2 I -OC(CH3)3Br -O (CH2) 3CH3 Br -OCH2CH (CH3) 2 -OCH3 I -OCH2CH3 I -OCH (CH3) 2 I -O (CH2) 3CH3 I -OCH2CH (CH3) 2 I -OC (CH3) 3
B. Ved at følge fremgangsmåden ifølge ^eksempel 3BB. Following the procedure of Example 3B
30 og anvende det angivne 1,2-benzisosulfonaz©3. og det angivne hydrid, den angivne reaktionstempera tur og det angivne opløsningsmiddel fremstilles Æet tilsvarende alkyl-4-hydroxy-2-methyl-2H-l,2-benzBthiazin-3-carboxylat-1,1-dioxid: 35 1230 and use the indicated 1,2-benzisosulfonaz © 3. and the indicated hydride, reaction temperature and solvent are prepared. A corresponding alkyl-4-hydroxy-2-methyl-2H-1,2-benz-thiazine-3-carboxylate-1,1-dioxide is prepared: 12
DK 15 413 9 BDK 15 413 9 B
OISLAND
H ,£Κ 0Η MLtalhy4rldJJ ► Al”1 *JL^ / 3 opløsningsmiddel ^ 5 XCH.H, £ Κ 0Η MLtalhy4rldJJ ► Al ”1 * JL ^ / 3 solvent ^ 5 XCH.
2 °2 *2 ° 2 *
Metal- X R1__ hydrid .· Temp. °C. Opløsningsmiddel 10 Cl -OCH3 KH 25 DMF1Metal X X Hydride · Temp. ° C. Solvent 10 Cl -OCH3 KH 25 DMF1
Cl -OCH2CH3 NaH 30 DMAC2Cl -OCH2CH3 NaH DMAC2
Cl -0(CH2)2CH3 NaH 35 DMFCl-O (CH2) 2CH3 NaH 35 DMF
Cl -OCH(CH3)2 CaH2 50 DMSO3Cl -OCH (CH3) 2 CaH2 50 DMSO3
Cl -0(CH2)3CH3 NaH 45 DMACCl-O (CH2) 3CH3 NaH 45 DMAC
15 Cl -OC(CH3)3 KH 30 HMPA4Cl -OC (CH3) 3 KH 30 HMPA4
Cl ->OCH2CH(CH3)2 KH 25 1-M-2-P"Cl -> OCH2CH (CH3) 2 KH 1-M-2-P "
Br -OCH3 NaH 35 DMFBr -OCH3 NaH 35 DMF
ΒΓ -OCH2CH3 KH 35 DMFΒΓ -OCH2CH3 KH 35 DMF
Br -0(CH2)3CH3 KH 25 DMACBr-O (CH2) 3CH3 KH DMAC
20 Br -0{CH2)2CH3 CaH2 45 DMSOBr-O (CH2) 2CH3 CaH2 DMSO
Br -OCH2CH(CH3)2 NaH 50 1-M-2-PBr -OCH2CH (CH3) 2 NaH 50 1-M-2-P
I -OCH3 KH 40 DMFI -OCH3 KH 40 DMF
I -OCH2CH3 NaH 40 HMPAI -OCH2CH3 NaH 40 HMPA
I -OCH(CH3) KH 35 DMSOI -OCH (CH 3) KH DMSO
25 I -0(CH2)3CH3 CaH2 50 DMSOI -0 (CH2) 3CH3 CaH2 50 DMSO
I -0CH2CH(CH3) NaH 30 DMACI -CH2CH (CH3) NaH DMAC
I -0C(CH3)3 KH 25 DMFI -0C (CH3) 3 KH DMF
*DMF = dimethylformamid 2 30 DMAC = dimethylacetamid 3DMSO = dimethylsulfoxid 4 HMPA = hexamethylphosphoramid 3l-M-2-P = l-methyl-2-pyrrolidon 35* DMF = dimethylformamide 2 DMAC = dimethylacetamide 3DMSO = dimethylsulfoxide 4 HMPA = hexamethylphosphoramide 3L-M-2-P = 1-methyl-2-pyrrolidone 35
Claims (3)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30874681 | 1981-10-05 | ||
| US06/308,746 US4376204A (en) | 1981-10-05 | 1981-10-05 | 3-Hydroxy 2-methyl benzisothiazolines as intermediates in production of piroxicam |
| US41303682A | 1982-09-02 | 1982-09-02 | |
| US41303682 | 1982-09-02 |
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| Publication Number | Publication Date |
|---|---|
| DK204888A DK204888A (en) | 1988-04-14 |
| DK204888D0 DK204888D0 (en) | 1988-04-14 |
| DK154139B true DK154139B (en) | 1988-10-17 |
| DK154139C DK154139C (en) | 1989-03-06 |
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| DK439482A DK154646C (en) | 1981-10-05 | 1982-10-04 | PROCEDURE FOR MANUFACTURING PIROXICAM AND INTERMEDIATES PROVIDING THIS RELATIONSHIP |
| DK204888A DK154139C (en) | 1981-10-05 | 1988-04-14 | METHOD FOR PREPARING 4-HYDROXY-2-METHYL-2H-1,2-BENZOTHIAZINE-1,1-DIOXIDE-3-CARBOXYLIC ACID DERIVATIVES CONVERSIBLE TO PIROXICAM |
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| DK439482A DK154646C (en) | 1981-10-05 | 1982-10-04 | PROCEDURE FOR MANUFACTURING PIROXICAM AND INTERMEDIATES PROVIDING THIS RELATIONSHIP |
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| DE (1) | DE3262440D1 (en) |
| DK (2) | DK154646C (en) |
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| ES (2) | ES516208A0 (en) |
| FI (1) | FI75342C (en) |
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| US3591584A (en) * | 1968-08-27 | 1971-07-06 | Pfizer | Benzothiazine dioxides |
| US3853862A (en) * | 1973-04-23 | 1974-12-10 | Pfizer | Production of 4-hydroxy-1,2-benzothiazine-3-carboxamides |
| US3891637A (en) * | 1974-10-01 | 1975-06-24 | Pfizer | Process for the production of carboxamides of oxo-1,2-benzothiazine-1,1-dioxides |
| US3892740A (en) * | 1974-10-15 | 1975-07-01 | Pfizer | Process for the production of carboxamides of oxo-1,2-benzothiazine-1,1-dioxides |
| US3960856A (en) * | 1975-06-20 | 1976-06-01 | Warner-Lambert Company | Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide |
| SE421792B (en) * | 1976-01-12 | 1982-02-01 | Pfizer | PROCEDURE FOR PREPARING N- (2-PYRIDYL) -4-HYDROXY-2-METHYL-2H-1,2-BENZO-THIAZINE-3-CARBOXAMIDE-1,1-DIOXIDE |
| US4074048A (en) * | 1976-05-10 | 1978-02-14 | Warner-Lambert Company | Process for the preparation of 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides |
| US4100347A (en) * | 1976-06-10 | 1978-07-11 | Pfizer Inc. | 3,4-Dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide |
| US4289879A (en) * | 1980-09-29 | 1981-09-15 | Pfizer Inc. | Synthetic method and intermediate for piroxicam |
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-
1984
- 1984-06-07 PH PH30790-AA patent/PH19297A/en unknown
- 1984-09-10 YU YU1560/84A patent/YU42903B/en unknown
-
1987
- 1987-03-09 SG SG229/87A patent/SG22987G/en unknown
- 1987-07-09 HK HK526/87A patent/HK52687A/en unknown
- 1987-12-30 MY MY510/87A patent/MY8700510A/en unknown
-
1988
- 1988-04-14 DK DK204888A patent/DK154139C/en not_active IP Right Cessation
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| Date | Code | Title | Description |
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| PBP | Patent lapsed |